The broad objective of this proposal is to determine mechanisms of action of the clinically useful antidepressant and smoking cessation aid, bupropion. The underlying hypothesis driving this application is that a successful smoking cessation pharmacotherapy would at least include a blocking activity at monoamine transporters and c_413_nAChR subtype. This component will first determine the potential (_4132 nAChR antagonistic properties of selected bupropion, hydroxybupropion and 3-phenyltropane analogs (provided by Project # 1) on nicotinic acute effects in mice. Compounds found to possess in vitro functional blocking activity at DA and NE transporters and c_4132nAChR subtype (provided by Projects 1 &2) will be assessed for their ability to block the acute effects of nicotine on nociception, body temperature and locomotor activity in miceAnalogs with potency higher than that of bupropion will be selected for testing in the nicotine dependence models. These analogs will be evaluated in two nicotine dependence-related behaviors in mice that models subjective properties and physical dependence-producing effects of nicotine: drug discrimination and withdrawal signs. These findings also will allow relationships to be defined between effects of drugs on NET, DAT, or nAChR function in vitro provided in Projects 1 and 2 and drug efficacy in the nicotine dependence models, thus helping to correlate molecular target profiles with effects on nicotine dependence. Compounds showing partial or total substitution properties and reversing nicotine withdrawal signs will be subsequently tested in rat i.v. self-administration Out of this work leads for new medications development for treatment of nicotine dependence will come. Our studies will yield information concerning the biological targets (transporters and nicotinic receptors) involved in bupropion's therapeutic benefits and will improve the limited efficacy of the current smoking cessation pharmacological strategies.